Publications by authors named "Wenjing Cao"

53 Publications

Work-Related Musculoskeletal Disorders Among Hospital Midwives in Chenzhou, Hunan Province, China and Associations with Job Stress and Working Conditions.

Risk Manag Healthc Policy 2021 3;14:3675-3686. Epub 2021 Sep 3.

Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China.

Background: Midwives have a high risk of work-related musculoskeletal disorders (WMSDs), which are the leading cause of pain and disability. However, the association between job stress and WMSDs among midwives has not been studied. The aim of this project was to specifically describe relationships between the job stress and WMSDs among a sample of hospital midwives in Chenzhou, Hunan Province, China.

Methods: We conducted a cross-sectional study among a sample of 769 eligible midwives in the city of Chenzhou in Hunan Province, China from May 2018 to January 2019. All participants completed a questionnaire regarding the presence and severity of different pain symptoms and job stress assessed by the Korean occupational stress scale.

Results: A total of 597 participants responded (77.6%), and 491 (82.2%) reported that they had experienced WMSDs at some time over a 12-month period. The most common pain site was low back (72.7%), followed by the neck (52.8%) and shoulders (42.7%). We revealed that various aspects of job stress were associated with WMSDs in the current study, namely "Owing to my workload, I always feel time pressure" (OR, 2.05; 95% CI: 1.28-3.28), "My job has become increasingly overbearing" (OR, 2.34; 95% CI: 1.46-3.77), "My work requires long lasting concentration" (OR, 3.50; 95% CI: 2.13-5.74), "I have to do various jobs simultaneously", (OR, 3.15; 95% CI: 1.93-5.14)), "My work requires creativity" (OR, 2.15; 95% CI: 1.31-3.54), "My work requires a high level of skill or knowledge" (OR, 2.83; 95% CI: 1.67-4.80), "My supervisor is helpful in getting the job done" (OR, 0.53; 95% CI: 0.33-0.84), "I have someone who understands my difficulties at work" (OR, 0.53; 95% CI: 0.34-0.85), "Undesirable changes (ie, downsizing) will come to my job" (OR, 3.28; 95% CI: 2.01-5.77), "My company provides me with sufficient organizational support" (OR, 0.47; 95% CI: 0.29-0.74), "Departments cooperate each other without conflicts" (OR, 0.50; 95% CI: 0.32-0.80), "I am provided with the opportunity to develop my capacity" (OR, 0.57; 95% CI: 0.36-0.91) and "My company climate is authoritative and hierarchical" (OR: 3.21; 95% CI: 1.97-5.23).

Conclusion: Overall, this study suggests that job stress has an important influence on WMSDs among a sample of hospital midwives in Chenzhou, Hunan Province, China. Given the multifaceted nature of identified risk, a comprehensive approach to reduce this risk is clearly required and a job stress management program will be essential.
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http://dx.doi.org/10.2147/RMHP.S299113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423493PMC
September 2021

Proteomic Analysis of Rhesus Macaque Brain Explants Treated With Identifies Host GAP-43 as a Potential Factor Associated With Lyme Neuroborreliosis.

Front Cell Infect Microbiol 2021 10;11:647662. Epub 2021 Jun 10.

Department of Microbiology and Immunology, Kunming Medical University, Kunming, China.

Background: Lyme neuroborreliosis (LNB) is one of the most dangerous manifestations of Lyme disease, but the pathogenesis and inflammatory mechanisms are not fully understood.

Methods: Cultured explants from the frontal cortex of rhesus monkey brain (n=3) were treated with live (Bb) or phosphate-buffered saline (PBS) for 6, 12, and 24 h. Total protein was collected for sequencing and bioinformatics analysis. In addition, changes in protein expression in the explants over time following Bb treatment were screened.

Results: We identified 1237 differentially expressed proteins (DEPs; fold change ≥1.5 or ≤0.67, -value ≤0.05). One of these, growth-associated protein 43 (GAP-43), was highly expressed at all time points in the explants. The results of the protein-protein interaction network analysis of DEPs suggested that GAP-43 plays a role in the neuroinflammation associated with LNB. In HMC3 cells incubated with live Bb or PBS for 6, 12, and 24 h, real-time PCR and western blot analyses confirmed the increase of GAP-43 mRNA and protein, respectively.

Conclusions: Elevated GAP-43 expression is a potential marker for LNB that may be useful for diagnosis or treatment.
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http://dx.doi.org/10.3389/fcimb.2021.647662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224226PMC
July 2021

Anti-inflammatory activity of different isolated sites of in complete Freund's adjuvant-induced arthritic rats.

Exp Ther Med 2021 Aug 8;22(2):848. Epub 2021 Jun 8.

Pharmacy Teaching and Research Department, College of Pharmacy, Wannan Medical College, Wuhu, Anhui 241002, P.R. China.

is a traditional Chinese medicine for treating arthritis and bruises. The aim of the present study was to investigate the anti-arthritic activities and possible associated mechanisms of different isolated sites of (DISC) in adjuvant-induced arthritis (AA) rats. The therapeutic effects of the extracts were assessed through changes in body weights, swelling rates, arthritis indexes (AI) and organ indexes. The levels of nitric oxide (NO), malondialdehyde and superoxide dismutase were determined using one-step method, TBA method and hydroxylamine method, respectively; the levels of TNF-α, IL-1β, IL-6, prostaglandin E, macrophage inhibitor factor-1, VEGF, immunoglobulin (Ig) G, IgM and IFN-γ in serum were determined using ELISA. Pathological changes and positive expression of VEGF in the ankle joints were investigated using hematoxylin-eosin staining and immunohistochemical staining, respectively. DISC treatment increased the weight gains and thymus indexes, and decreased the swelling rates, spleen indexes and AI in AA rats. The water isolated site (WA) and ethyl acetate isolated site (EA) significantly reversed complete Freund's adjuvant (CFA)-induced changes in the levels of NO, IL-6, TNF-α, IgG and IFN-γ, while the n-butanol isolated site (NB) only reversed the changes in IL-6 and IgG contents. Some changes in the chloroform isolated site group showed the same trend as those in the model group. The extracts relieved synovial hyperplasia, inflammatory cell infiltration and articular surface defects, and reduced the positive expression rate of VEGF in the synovial tissues of the AA rats to varying degrees. The WA exhibited the most marked effects, followed by the EA and NB, indicating that WA had optimal therapeutic effects on CFA-induced arthritic rats, which may be mediated by the oxidative stress and inhibition of inflammatory factors. may serve as a potential candidate for the treatment of rheumatoid arthritis.
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http://dx.doi.org/10.3892/etm.2021.10280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210295PMC
August 2021

Characteristics of inflammatory phenotypes among patients with asthma: relationships of blood count parameters with sputum cellular phenotypes.

Allergy Asthma Clin Immunol 2021 May 11;17(1):47. Epub 2021 May 11.

Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, 130041, Jilin, China.

Background: There is a need to identify the asthma inflammatory phenotypes of patients to facilitate personalized asthma treatment. Sputum induction is time-consuming and requires expert clinical technique. This study aimed to assess the distribution and characteristics of asthma inflammatory phenotypes in Jilin Province, China; it also aimed to identify an easier method for characterization of an asthma phenotype, rather than sputum cellular analysis.

Methods: In this study, 232 asthma patients underwent sputum induction following clinical assessment and blood collection. Inflammatory cell counts in sputum were used to classify asthma inflammatory phenotypes. Receiver operating characteristic curve and Spearman correlation coefficient analyses were used to identify correlations between clinical parameters.

Results: Among the included patients, there had 52.1% paucigranulocytic, 38.4% eosinophilic, 4.3% neutrophilic, and 5.2% mixed granulocytic asthma phenotypes, respectively. In total, 129 (55.6%) patients had asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO); these patients had higher proportion of smokers, higher sputum neutrophil count, worse lung function, and worse asthma control, compared with patients who had asthma alone (p < 0.05). Sputum eosinophil/neutrophil counts were positively correlated with blood eosinophil/neutrophil counts (p < 0.01). To identify the presence of sputum eosinophil proportion ≥ 3%, optimal cut-off values for blood eosinophil count and fractional exhaled nitric oxide (FeNO) were 0.2 × 10/L and 30.25 ppd (area under the curve (AUC) = 0.744; AUC = 0.653, p < 0.001). AUCs did not significantly differ between FeNO and blood eosinophil count (p = 0.162), but both exhibited poor specificity (57% and 49%, respectively). To identify the presence of sputum neutrophil proportion ≥ 61%, the optimal cut-off value for blood neutrophil proportion was 69.3% (AUC = 0.691, p = 0.0003); however, this exhibited poor sensitivity (50%).

Conclusions: Paucigranulocytic asthma was the most common phenotype, followed by eosinophilic asthma. Higher proportion of smokers, poor patient compliance, insufficient treatment, and poor asthma control may have been the main causes of high ACO proportion among patients in this study. Blood eosinophil/neutrophil counts exhibited poor specificity and sensitivity for prediction of airway eosinophilic/neutrophilic inflammation.
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http://dx.doi.org/10.1186/s13223-021-00548-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111745PMC
May 2021

Dietary proanthocyanidins alleviated ovarian fibrosis in letrozole-induced polycystic ovary syndrome in rats.

J Food Biochem 2021 05 5;45(5):e13723. Epub 2021 Apr 5.

Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.

This study investigated the effects of proanthocyanidins (PCs) on ovarian fibrosis in letrozole-induced polycystic ovary syndrome (PCOS) in rats. The administration of PCs effectively reduced the body weight (BW) and relative ovarian weight in PCOS rats. ELISA results revealed that PCs significantly reduced the level of serum T, LH, LH/FSH in the PCOS group. In addition, qRT-PCR results revealed that treatment with PCs significantly increased the main antioxidant enzymes (Cat, Sod2, Gpx3, Mgst1, Gsta4, Sod1 and Prdx3) in PCOS rats. Also, the expression analysis of proteins by Western blotting revealed that PCs significantly decreased the level of TGF-βR1, p-Smad3, p-Smad2 and Smad4 and reversed the downregulation of Smad7 in PCOS rats. The study suggested that PCs improved ovarian fibrosis in PCOS rats by regulating the serum hormone level, inhibiting oxidative stress and suppressing the activation of the TGF-β1/Smads signaling pathway. PRACTICAL APPLICATIONS: Currently, plant extracts are being widely used to treat female reproductive and metabolic disorders. Particularly, proanthocyanidins (PCs), the well-known natural polyphenolic compounds, which are a significant source of antioxidants present in many colored fruits, are consumed as fruits as well as a dietary supplement to prevent many disorders. Recent pharmacological studies have reported that PCs have many health beneficial properties, such as antioxidant activity, improving cholesterol homeostasis, blood lipid regulatory properties, microcirculation improvement effect, antitumor activity and anti-aging activity. Despite these properties of PCs, the antifibrosis effect of PCs has not been studied to date. The main purpose of this study was to research the role and the mechanisms of PCs in ovarian fibrosis in PCOS rats.
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http://dx.doi.org/10.1111/jfbc.13723DOI Listing
May 2021

Massive Open Online Courses-based blended versus face-to-face classroom teaching methods for fundamental nursing course.

Medicine (Baltimore) 2021 Mar;100(9):e24829

Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.

Abstract: An increasing number of studies focus on the effectiveness of Massive Open Online Courses (MOOC)-based blended learning, whereas none have yet studied using it for teaching fundamental nursing skills at an undergraduate level.To evaluate the effectiveness of MOOC-based blended learning versus face-to-face classroom teaching techniques within the fundamental nursing course at the Faculty of Nursing, University of Xiang Nan, China.This cluster randomized controlled trial enrolled 181 students and assigned them into either an MOOC-based blended or a face-to-face classroom teaching group, both involving the Fundamental Nursing course for undergraduate nursing students. The analyzed outcomes included test scores, critical thinking ability, and feedback received from the students on the Fundamental Nursing course.MOOC-based blended techniques versus face-to-face classroom teaching methods demonstrated higher daily performance (P = .014), operational performance (P = .001), theoretical achievements (P < .001), and final grades (P < .001) in Fundamental Nursing.Moreover, the mean change in the participants' critical thinking ability items between groups were, mostly, statistically significant. The items focusing on the feedback from the students demonstrated significant differences between the groups in terms of their satisfaction with the teaching they received (P < .001) and the overall learning effects (P = .030).This study confirmed that receiving MOOC-based blended learning was superior when compared against face-to-face classroom teaching techniques for learning within the Fundamental Nursing course.
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http://dx.doi.org/10.1097/MD.0000000000024829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939164PMC
March 2021

Analytical evaluation of Reebio procalcitonin latex-enhanced immunoturbidimetric assay on the HITACHI Labospect 008AS.

Clin Chem Lab Med 2020 11 23;59(1):e23-e26. Epub 2020 Nov 23.

Department of Laboratory Medicine, The Fifth Medical Center, Chinese PLA General Hospital (Former 307th hospital of the PLA), Beijing, P.R. China.

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http://dx.doi.org/10.1515/cclm-2020-0796DOI Listing
November 2020

Lung organoids, useful tools for investigating epithelial repair after lung injury.

Stem Cell Res Ther 2021 01 30;12(1):95. Epub 2021 Jan 30.

The Institute for Tropical Medicine, Kunming Medical University, Kunming, 650500, Yunnan, China.

Organoids are derived from stem cells or organ-specific progenitors. They display structures and functions consistent with organs in vivo. Multiple types of organoids, including lung organoids, can be generated. Organoids are applied widely in development, disease modelling, regenerative medicine, and other multiple aspects. Various human pulmonary diseases caused by several factors can be induced and lead to different degrees of lung epithelial injury. Epithelial repair involves the participation of multiple cells and signalling pathways. Lung organoids provide an excellent platform to model injury to and repair of lungs. Here, we review the recent methods of cultivating lung organoids, applications of lung organoids in epithelial repair after injury, and understanding the mechanisms of epithelial repair investigated using lung organoids. By using lung organoids, we can discover the regulatory mechanisms related to the repair of lung epithelia. This strategy could provide new insights for more effective management of lung diseases and the development of new drugs.
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http://dx.doi.org/10.1186/s13287-021-02172-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846910PMC
January 2021

Minimal Essential Human Factor VIII Alterations Enhance Secretion and Gene Therapy Efficiency.

Mol Ther Methods Clin Dev 2020 Dec 22;19:486-495. Epub 2020 Oct 22.

Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA.

One important limitation for achieving therapeutic expression of human factor VIII (FVIII) in hemophilia A gene therapy is inefficient secretion of the FVIII protein. Substitution of five amino acids in the A1 domain of human FVIII with the corresponding porcine FVIII residues generated a secretion-enhanced human FVIII variant termed B-domain-deleted (BDD)-FVIII-X5 that resulted in 8-fold higher FVIII activity levels in the supernatant of an cell-based assay system than seen with unmodified human BDD-FVIII. Analysis of purified recombinant BDD-FVIII-X5 and BDD-FVIII revealed similar specific activities for both proteins, indicating that the effect of the X5 alteration is confined to increased FVIII secretion. Intravenous delivery in FVIII-deficient mice of liver-targeted adeno-associated virus (AAV) vectors designed to express BDD-FVIII-X5 or BDD-FVIII achieved substantially higher plasma FVIII activity levels for BDD-FVIII-X5, even when highly efficient codon-optimized nucleotide sequences were employed. A comprehensive immunogenicity assessment using stimulation assays and various preclinical models of hemophilia A demonstrated that the BDD-FVIII-X5 variant does not exhibit an increased immunogenicity risk compared to BDD-FVIII. In conclusion, BDD-FVIII-X5 is an effective FVIII variant molecule that can be further developed for use in gene- and protein-based therapeutics for patients with hemophilia A.
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http://dx.doi.org/10.1016/j.omtm.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708868PMC
December 2020

Predictive performance of interferon-γ release assays and tuberculin skin tests - Authors' reply.

Lancet Infect Dis 2020 12 25;20(12):1372-1373. Epub 2020 Nov 25.

Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(20)30872-0DOI Listing
December 2020

Plasma levels of S100A8/A9, histone/DNA complexes, and cell-free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura.

J Thromb Haemost 2021 02 3;19(2):370-379. Epub 2021 Jan 3.

Division of Laboratory Medicine, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening blood disorder, primarily resulting from autoantibodies against ADAMTS13. Infection or inflammation often precedes acute iTTP. However, the association of inflammation and inflammatory mediators with disease severity and outcome of acute iTTP is not fully assessed.

Objectives: Here, we determined plasma levels of S100A8/A9, histone/DNA complexes, citrullinated histone H3 (CitH3), and cell-free DNA (cfDNA) in a cohort of 108 acute episodes from 94 unique iTTP patients and healthy controls, and assessed the association of each of these biomarkers with the disease severity and mortality.

Results: All acute iTTP patients had significantly increased plasma levels of S100A8/A9 (median 84.8, interquartile range [IQR] 31.2-157.4 µg/mL), histone/DNA complexes (median 55.7, IQR 35.8-130.8 U/mL), CitH3 (median 3.8, IQR 2.2-6.4 ng/mL), and cfDNA (median 937.7, IQR 781.3-1420.0 ng/mL) on the admission blood samples when compared with healthy controls. An increased plasma level of S100A8/A9, histone/DNA complex and cfDNA was associated with organ damage, coagulopathy, and mortality in iTTP. After being adjusted for age and history of hypertension, Cox proportional hazard regression analysis demonstrated that a hazard ratio (95% confidence interval) for an elevated plasma level of S100A8/A9, histone/DNA complexes, and cfDNA was 11.5 (1.4-90.9) (P = .021), 10.3 (2.7-38.5) (P = .001), and 12.8 (3.9-42.0) (P = .014), respectively.

Conclusion: These results indicate that inflammation or plasma inflammatory mediators such as S100A8/A9 or NETosis markers such as histone/DNA complexes and cfDNA may play a role in pathogenesis of iTTP, which may help stratify patients with a high risk of death during acute iTTP episodes.
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http://dx.doi.org/10.1111/jth.15176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058879PMC
February 2021

Exome Sequencing Identifies Abnormalities in Glycosylation and ANKRD36C in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura.

Thromb Haemost 2021 Apr 12;121(4):506-517. Epub 2020 Nov 12.

Department of Pathology & Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, United States.

Background:  Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). However, the mechanism underlying anti-ADAMTS13 autoantibody formation is not known, nor it is known how genetic aberrations contribute to the pathogenesis of iTTP.

Methods:  Here we performed whole exome sequencing (WES) of DNA samples from 40 adult patients with iTTP and 15 local healthy subjects with no history of iTTP and other hematological disorders.

Results:  WES revealed variations in the genes involved in protein glycosylation, including O-linked glycosylation, to be a major pathway affected in patients with iTTP. Moreover, variations in the gene family, particularly and its paralogs, were also more prevalent in patients with iTTP than in the healthy controls. The ANKRD36 family of proteins have been implicated in inflammation. Mass spectrometry revealed a dramatic alternation in plasma glycoprotein profile in patients with iTTP compared with the healthy controls.

Conclusion:  Altered glycosylation may affect the disease onset and progression in various ways: it may predispose patients to produce ADAMTS13 autoantibodies or affect their binding properties; it may also alter clearance kinetics of hemostatic and inflammatory proteins. Together, our findings provide novel insights into plausible mechanisms underlying the pathogenesis of iTTP.
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http://dx.doi.org/10.1055/s-0040-1719030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091491PMC
April 2021

Overexpression of NCAPG inhibits cardia adenocarcinoma apoptosis and promotes epithelial-mesenchymal transition through the Wnt/β-catenin signaling pathway.

Gene 2021 Jan 24;766:145163. Epub 2020 Sep 24.

Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China. Electronic address:

Background: Cardia adenocarcinoma (CA) is a distinct form of gastric cancer, and the optimal means of treating it remains controversial. At present, the role of the condensation complex gene non-SMC condensin I complex subunit G (NCAPG) in CA is uncertain, and as such the present study was designed to elucidate its importance in this oncogenic context.

Methods: We first used bioinformatics approaches to assess NCAPG expression profiles in CA using public databases. Protein profiling was also used to examine the expression of this protein in CA tumors and adjacent tissues from 20 patients. Then the expression of NCAPG in CA samples was quantified via qRT-PCR and Western blotting. NCAPG knockdown and overexpression in the SGC-7901 and AGS cell lines were subsequently performed, after which the expression of key proteins associated with epithelial-mesenchymal transition (EMT; E-cadherin, vimentin, N-cadherin, Snail, Slug) and the regulation of apoptotic responses (caspase-3, Bax, Bcl-2) was measured. The mechanistic role of NCAPG in CA was additionally studied by analyzing proteins associated with Wnt/β-catenin signaling including Wnt1, phosphorylated GSK3β, β-catenin, and phosphorylated β- catenin. The impact of NCAPG on the migration, survival, and invasion of CA cells was further examined.

Results: CA samples exhibited high NCAPG expression. When this gene was overexpressed in cell lines, it reduced caspase-3, Bax, and E-cadherin levels whereas it elevated Bcl-2, vimentin, N-cadherin, Snail, and Slug levels. NCAPG overexpression also resulted in the enhanced expression of Wnt1, phosphorylated GSK3β, and total β-catenin and the reduced expression of phosphorylated β-catenin. The knockdown of NCAPG, in contrast, yielded the opposite phenotype. At a functional level, the overexpression of NCAPG improved the apoptotic resistance of CA cells while driving them to undergo EMT and to become more invasive and migratory.

Conclusions: NCAPG overexpression can promote EMT and suppress tumor cell apoptosis via the activation of Wnt/β-catenin signaling.
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http://dx.doi.org/10.1016/j.gene.2020.145163DOI Listing
January 2021

Efficacy and Safety of Antibiotics for Treatment of Scrub Typhus: A Network Meta-analysis.

JAMA Netw Open 2020 08 3;3(8):e2014487. Epub 2020 Aug 3.

Institute for Tropical Medicine, Kunming Medical University School of Basic Medical Sciences, Kunming, China.

Importance: Antibiotics have been used for many years to treat scrub typhus, but their efficacy and safety have not been studied thoroughly.

Objective: To compare and rank different antibiotics to identify which one can safely eliminate Orientia tsutsugamushi and efficiently alleviate fever in patients with scrub typhus.

Data Sources: An electronic search of PubMed and Embase was conducted, from database inception to July 12, 2019. The study was conducted from July 12 to September 2, 2019.

Study Selection: Randomized clinical trials and retrospective studies that evaluated the use of antibiotics for treatment in patients diagnosed with scrub typhus caused by O tsutsugamushi were included. Records of articles in English were considered eligible. Studies were assessed independently by 2 reviewers, with disagreement resolved by consensus. Of 6408 studies initially identified, 10 randomized clinical trials and 4 retrospective study met the criteria for further analysis.

Data Extraction And Synthesis: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension statement for systematic reviews incorporating network meta-analyses of health care interventions. Data were independently extracted by 2 reviewers and synthesized with frequentist random-effects network meta-analyses.

Main Outcomes And Measures: The primary outcome was efficacy of the antibiotic, considered as the number of patients who achieved complete healing with an antibiotic. Safety, defined as the prevalence of adverse events associated with the antibiotics, was the secondary outcome, and defervescence time was the tertiary outcome. P scores (scale of 0 to 1, with 1 indicating superiority to other treatments) were used to rank the efficacy, safety, and defeverescence time of the antibiotics.

Results: Three searches for articles in Embase and PubMed identified 10 randomized clinical trials (888 participants) and 4 retrospective studies (323 participants) for further analyses. No particular treatment regimen showed a significant advantage or disadvantage with regard to efficacy or safety. However, meta-analysis of retrospective studies indicated that clarithromycin (P score = 0.8730) alleviated fever more efficiently than other antibiotics.

Conclusions And Relevance: No treatment regimen reported in this network meta-analysis showed a significant advantage or disadvantage with regard to efficacy or safety. However, clarithromycin might be a better choice than the other drugs for alleviating fever.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.14487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455851PMC
August 2020

Isoforskolin and Cucurbitacin IIa promote the expression of anti-inflammatory regulatory factor SIGIRR in human macrophages stimulated with Borrelia burgdorferi basic membrane protein A.

Int Immunopharmacol 2020 Nov 20;88:106914. Epub 2020 Aug 20.

Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China; Yunnan Province Key Laboratory of Children's Major Diseases Research, The Children's Hospital of Kunming/Kunming Medical University, Kunming 650030, China; The Institute for Tropical Medicine, Kunming Medical University, Kunming 650500, China; Yunnan Demonstration Base of International Science and Technology Cooperation for Tropical Diseases, Kunming 650500, China. Electronic address:

Certain natural products, derived from medicinal plants, exhibit anti-inflammatory properties, but the mechanism of action of many remains unclear. Borrelia burgdorferi spirochetes are responsible for causing Lyme arthritis through activation of the Toll-like receptor (TLR) signaling pathway. In this study, we investigated the mechanisms by which Isoforskolin (ISOF) and Cucurbitacin IIa (CuIIa), compounds derived from Chinese herbs, can exert anti-inflammatory effects by modulating single immunoglobulin interleukin-1 receptor-related receptor (SIGIRR; also known as Toll/interleukin-1 receptor 8, TIR8) and thereby inhibiting B. burgdorferi basic membrane protein A (BmpA)-induced TLR signaling in human macrophages, specifically the THP-1 human monocytic cell line. After THP-1 cells were exposed in vitro to: i) recombinant (r)BmpA, ii) rBmpA and ISOF or iii) rBmpA and CuIIa, Cytotoxicity assay (Cell Counting Kit-8, CCK-8) are used to measure the effects of ISOF and CuIIa on cell viability. Meanwhile, real-time polymerase chain reaction and Western blotting were used to quantify SIGIRR mRNA and protein levels, respectively, at 6, 12, 24 and 48 h time points post-stimulation. In addition, proinflammatory cytokine tumor necrosis factor-α (TNF-α) was determined by ELISA analysis. Our study showed that rBmpA stimulation of THP-1 cells resulted in a drop in SIGIRR levels in THP-1 cells. More importantly, SIGIRR levels increased significantly in rBmpA-stimulated THP-1 cells following ISOF or CuIIa administration, and the results of ELISA analysis suggested that ISOF or CuIIa reduced the secretion of the proinflammatory cytokine TNF-α. In conclusion, These results reveal new possibilities for the treatment of Lyme arthritis.
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http://dx.doi.org/10.1016/j.intimp.2020.106914DOI Listing
November 2020

Design and Performance Evaluation of a Deep Neural Network for Spectrum Recognition of Underwater Targets.

Comput Intell Neurosci 2020 1;2020:8848507. Epub 2020 Aug 1.

Tianjin Jinhang Computing Technology Research Institute, Tianjin, China.

Due to the complexity of the underwater environment, underwater acoustic target recognition (UATR) has always been challenging. Although deep neural networks (DNN) have been used in UATR and some achievements have been made, the performance is not satisfactory when recognizing underwater targets with different Doppler shifts, signal-to-noise ratios (SNR), and interferences. In the paper, a one-dimensional convolutional neural network (1D-CNN) was proposed to recognize the line spectrums of Detection of Envelope Modulation on Noise (DEMON) spectrums of underwater target-radiated noise. Datasets of targets with different Doppler shifts, SNRs, and interferences were designed to evaluate the generalization performance of the proposed CNN. Experimental results show that compared with traditional multilayer perceptron (MLP) networks, the 1D-CNN model better performs in recognition of targets with different Doppler shifts and SNRs. The outstanding generalization ability of the proposed model shows that it is suitable for practical engineering applications.
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http://dx.doi.org/10.1155/2020/8848507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416231PMC
July 2021

Coagulation Dysfunction.

Arch Pathol Lab Med 2020 10;144(10):1223-1229

the Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City (Liu, Cao).

Context.—: The coronavirus disease 2019 (COVID-19) is a highly contagious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coagulation dysfunction is a hallmark in patients with COVID-19. Fulminant thrombotic complications emerge as critical issues in patients with severe COVID-19.

Objective.—: To present a review of the literature and discuss the mechanisms of COVID-19 underlying coagulation activation and the implications for anticoagulant and thrombolytic treatment in the management of COVID-19.

Data Sources.—: We performed a systemic review of scientific papers on the topic of COVID-19, available online via the PubMed NCBI, medRxiv, and Preprints as of May 15, 2020. We also shared our experience on the management of thrombotic events in patients with COVID-19.

Conclusions.—: COVID-19-associated coagulopathy ranges from mild laboratory alterations to disseminated intravascular coagulation (DIC) with a predominant phenotype of thrombotic/multiple organ failure. Characteristically, high D-dimer levels on admission and/or continuously increasing concentrations of D-dimer are associated with disease progression and poor overall survival. SARS-CoV-2 infection triggers the immune-hemostatic response. Drastic inflammatory responses including, but not limited to, cytokine storm, vasculopathy, and NETosis may contribute to an overwhelming activation of coagulation. Hypercoagulability and systemic thrombotic complications necessitate anticoagulant and thrombolytic interventions, which provide opportunities to prevent or reduce "excessive" thrombin generation while preserving "adaptive" hemostasis and bring additional benefit via their anti-inflammatory effect in the setting of COVID-19.
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http://dx.doi.org/10.5858/arpa.2020-0324-SADOI Listing
October 2020

Factor VIII binding affects the mechanical unraveling of the A2 domain of von Willebrand factor.

J Thromb Haemost 2020 09 23;18(9):2169-2176. Epub 2020 Jul 23.

Department of Bioengineering, Lehigh University, Bethlehem, PA, USA.

Background: Proteolytic cleavage of von Willebrand factor (VWF) by ADAMTS13 is crucial for normal hemostasis. Our previous studies demonstrate that binding of coagulation factor VIII (or FVIII) to VWF enhances the proteolytic cleavage of VWF by ADAMTS13 under shear.

Objectives: Present study aims to determine the mechanism underlying FVIII-mediated enhancing effect on VWF proteolysis by ADAMTS13 under force.

Methods: Single molecular force spectroscopy, atomic force microscopy, and surface plasmon resonance are all used.

Results: Using single molecule force spectroscopy, we show that an addition of FVIII (~5 nmol/L) to D'D3 or D'D3A1 does not significantly alter force-induced unfolding of these fragments; however, an addition of FVIII at the same concentration to D'D3A1A2 eliminates its long unfolding event at ~40 nm, suggesting that binding of FVIII to D'D3 and/or A2 may result in force-induced conformational changes in A2 domain. Atomic force spectroscopy further demonstrates the direct binding between FVIII and D'D3 (or A2) with an intrinsic 2-dimensional off-rate (k ) of 0.02 ± 0.01/s (or 0.3 ± 0.1/s). The direct binding interaction between FVIII and A2 is further confirmed with the surface plasmon resonance assay, with a dissociation constant of ~0.2 μmol/L; no binding is detected between FVIII and A1 under the same conditions.

Conclusions: Our results suggest that binding of FVIII to D'D3 and/or A2 may alter the mechanical property in the central A2 domain. The findings provide novel insight into the molecular mechanism underlying FVIII-dependent regulation of VWF proteolysis by ADAMTS13 under mechanical force.
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http://dx.doi.org/10.1111/jth.14962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789802PMC
September 2020

Prevalence of Percutaneous Injuries and Associated Factors Among a Sample of Midwives in Hunan Province, China.

Workplace Health Saf 2020 Sep 29;68(9):422-431. Epub 2020 May 29.

The Second Affiliated Hospital of Guangzhou University of Chinese Medicine.

Percutaneous injuries and blood-borne-related infections pose occupational hazards to healthcare professionals. However, the prevalence and associated factors for these hazards among midwives in Hunan Province, China are poorly documented. : A cross-sectional study was conducted among a sample of 1,282 eligible midwives in the cities of Yongzhou, Chenzhou, Hengyang, and Changsha in Hunan Province, China, from January 2017 to July 2017. The association of selected independent variables with percutaneous injuries was investigated using binary logistic regression. : 992 participants responded (77.3%), and within the previous 12 months, 15.7% experienced percutaneous injuries. In multivariate analysis, hospital size, age, length of employment as a midwife, weekly working hours, and three aspects of Hospital Safety Climate Scale were associated with percutaneous injuries. The risk of percutaneous injuries among the midwives working in hospitals with ≤399 beds was higher than that among those working in hospitals with ≥400 beds by nearly 3 times. Furthermore, the percutaneous injury prevalence of midwives decreased as age increased. Moreover, the probability of percutaneous injuries among the midwives with weekly working hours of >40 was 4.35 times higher compared with that among midwives with weekly working hours of ≤40. : The prevalence of percutaneous injuries among midwives in the study hospitals was substantial. Our results further proved that risk mitigation strategies tailored to midwives are needed to reduce this risk. These strategies include ensuring a positive organizational climate, providing highly safe devices, and reducing the workload.
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http://dx.doi.org/10.1177/2165079920914923DOI Listing
September 2020

Early Detection of Severe Acute Respiratory Syndrome Coronavirus 2 Antibodies as a Serologic Marker of Infection in Patients With Coronavirus Disease 2019.

Clin Infect Dis 2020 11;71(16):2066-2072

AnyGo Technology Co, Ltd, Beijing, China.

Background: Thousands of medical staff have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with hundreds of deaths reported. Such loss could be prevented if there were a serologic assay for SARS-CoV-2-specific antibodies for serological surveillance of its infection at the early stage of disease.

Methods: Using Chinese hamster ovarian (CHO) cell-expressed full-length SARS-CoV-2 S1 protein as capturing antigen, a coronavirus disease 2019 (COVID-19)/SARS-CoV-2 S1 serology enzyme-linked immunosorbent assay (ELISA) kit was developed and validated with negative samples collected prior to the outbreak or during the outbreak and positive samples from patients confirmed with COVID-19.

Results: The specificity of the ELISA kit was 97.5%, as examined against total 412 normal human samples. The sensitivity was 97.1% by testing against 69 samples from hospitalized and/or recovered COVID-19 patients. The overall accuracy rate reached 97.3%. The assay was able to detect SARS-CoV-2 antibody on day 1 after the onset of COVID-19 disease. The average antibody levels increased during hospitalization and 14 days after discharge. SARS-CoV-2 antibodies were detected in 28 of 276 asymptomatic medical staff and 1 of 5 nucleic acid test-negative "close contacts" of COVID-19 patients.

Conclusions: With the assays developed here, we can screen medical staff, incoming patients, passengers, and people who are in close contact with the confirmed patients to identify the "innocent viral spreaders," protect the medical staff, and stop further spread of the virus.
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http://dx.doi.org/10.1093/cid/ciaa523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197602PMC
November 2020

500 nm induced tunable syngas synthesis from CO photoreduction by controlling heterojunction concentration.

Chem Commun (Camb) 2020 May;56(40):5354-5357

State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China.

A heterostructured CoAl-layered double hydroxide/MoS2 nanocomposite photocatalyst (CoAl-LDH/MoS2) for CO2 photoreduction was prepared by simple electrostatic interactions. The syngas ratio (H2 : CO) was precisely tuned from 1.3 : 1 to 15 : 1 by altering only the catalyst concentration in the photocatalytic CO2 reduction system under visible light (λ > 400 nm). Interestingly, a rather high evolution rate can be obtained from CO2 photoreduction to CO up to 4575 μmol g-1 h-1 even under irradiation above 500 nm.
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http://dx.doi.org/10.1039/d0cc00971gDOI Listing
May 2020

Interleukin-17 in urine and serum of patients with nephritis.

Int J Rheum Dis 2020 May 23;23(5):706. Epub 2020 Apr 23.

Tareev Clinic, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.

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http://dx.doi.org/10.1111/1756-185X.13844DOI Listing
May 2020

Integrative Transcriptome and Proteome Analyses Provide New Insights Into the Interaction Between Live Borrelia burgdorferi and Frontal Cortex Explants of the Rhesus Brain.

J Neuropathol Exp Neurol 2020 05;79(5):518-529

From the Yunnan Province Key Laboratory for Tropical Infectious Diseases in Universities.

Borrelia burgdorferi (Bb), which is neurotropic, can attack the central nervous system (CNS), leading to the development of various neurologic symptoms. The pathogenesis of Lyme neuroborreliosis (LNB) remains poorly understood. Presently, there is a lack of knowledge of the changes in mRNA and proteins in the CNS following early disseminated Lyme disease. Explants from the frontal cortex of 3 rhesus brains were incubated with medium alone or with medium containing live Bb for 6, 12, or 24 hours. Then, we analyzed identified mRNA and proteins in the frontal cortex tissues, allowing for an in-depth view of the transcriptome and proteome for a macroscopic and unbiased understanding of early disseminated Lyme disease in the brain. Through bioinformatics analysis, a complex network of enriched pathways that were mobilized during the progression of Lyme spirochete infection was described. Furthermore, based on the analysis of omics data, translational regulation, glycosaminoglycan/proteoglycan-binding activity in colonization and dissemination to tissues, disease-associated genes, and synaptic function were enriched, which potentially play a role in pathogenesis during the interaction between frontal cortex tissues and spirochetes. These integrated omics results provide unbiased and comprehensive information for the further understanding of the molecular mechanisms of LNB.
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http://dx.doi.org/10.1093/jnen/nlaa015DOI Listing
May 2020

The seroprevalence of Anaplasma phagocytophilum in global human populations: A systematic review and meta-analysis.

Transbound Emerg Dis 2020 Mar 16. Epub 2020 Mar 16.

Department of Microbiology and Immunology, School of Basic Medical Sciences, Kunming Medical University, Kunming, China.

The tick-borne pathogen Anaplasma phagocytophilum is an emerging infectious disease threat, but the overall A. phagocytophilum seroprevalence in humans is unclear. We performed a systematic search of English databases for literature published from 1994 to 2018. Studies reporting serological evidence of A. phagocytophilum infection in humans were included, and the information was extracted by two authors independently. As the study heterogeneity was significant, a random-effects model was used to calculate the overall pooled seroprevalence. Data from 56 studies involving 28,927 individuals from four continents were included. The seroprevalence reported by the studies ranged from 0% to 37.26%. The overall pooled A. phagocytophilum seroprevalence in humans was 8.4% (95% CI: 6.6%-10.4%). The seroprevalence was highest in high-risk population (13.8%) and lowest in healthy population (5.0%). The estimated A. phagocytophilum seroprevalence of febrile patient, tick-bitten and tick-borne diseases populations was 6.4%, 8.0% and 9.0%, respectively. This meta-analysis demonstrated first A. phagocytophilum seroprevalence estimates in different populations (healthy, febrile patient, high-risk, tick-bitten and tick-borne diseases populations); it seems likely that present surveillance efforts are missing mild or asymptomatic infections of humans.
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http://dx.doi.org/10.1111/tbed.13548DOI Listing
March 2020

Identification of Key Coagulation Activity Determining Elements in Canine Factor VIII.

Mol Ther Methods Clin Dev 2020 Jun 15;17:328-336. Epub 2020 Jan 15.

Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA.

It is well known that canine factor VIII (cFVIII) has a higher specific activity than does human FVIII (hFVIII), and it has been previously demonstrated that cFVIII light chain is able to enhance hFVIII activity. The goal of this study was to first determine which amino acids in cFVIII light chain were responsible for enhancing hFVIII activity, and second to use these amino acids to develop a hFVIII variant with enhanced functional activity. We systemically screened segments of cFVIII light chain by testing an array of human-canine light chain hybrids and found that canine amino acids 1857-2147 were key to this enhancement. Each canine amino acid within this span was screened individually using a negative selection method, which led to the identification of 12 aa (JF12) in the FVIII light chain that could enhance activity. Substitution of the corresponding 12 aa into hFVIII (hFVIIIJF12BDD) elevated the specific activity profile . Furthermore, hFVIIIJF12BDD expressed an -displayed increased coagulation activity compared to wild-type, while maintaining normal secretion efficiency. In conclusion, we identified the amino acids in cFVIII that are the key determinants for higher specific activity and may be the basis for future development of therapeutic treatments for hemophilia A.
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http://dx.doi.org/10.1016/j.omtm.2019.12.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013134PMC
June 2020

Longitudinal assessments of plasma ADAMTS13 biomarkers predict recurrence of immune thrombotic thrombocytopenic purpura.

Blood Adv 2019 12;3(24):4177-4186

Division of Laboratory Medicine, Department of Pathology, and.

Immune thrombotic thrombocytopenic purpura (iTTP) is primarily caused by immunoglobulin G (IgG)-type autoantibodies that bind and inhibit plasma ADAMTS13 activity and/or accelerate its clearance from circulation. Approximately 50% of patients with iTTP who achieve initial clinical response to therapy experience recurrence (ie, exacerbation and/or relapse); however, a reliable biomarker that predicts such an event is currently lacking. The present study determines the role of longitudinal assessments of plasma ADAMTS13 biomarkers in predicting iTTP exacerbation/recurrence. Eighty-three unique iTTP patients with 97 episodes from the University of Alabama at Birmingham Medical Center between April 2006 and June 2019 were enrolled. Plasma levels of ADAMTS13 activity, antigen, and anti-ADAMTS13 IgG on admission showed no significant value in predicting iTTP exacerbation or recurrence. However, persistently low plasma ADAMTS13 activity (<10 U/dL; hazard ratio [HR], 4.4; 95% confidence interval [CI], 1.6-12.5; P = .005) or high anti-ADAMTS13 IgG (HR, 3.1; 95% CI, 1.2-7.8; P = .016) 3 to 7 days after the initiation of therapeutic plasma exchange was associated with an increased risk for exacerbation or recurrence. Furthermore, low plasma ADAMTS13 activity (<10 IU/dL; HR, 4.8; 95% CI, 1.8-12.8; P = .002) and low ADAMTS13 antigen (<25th percentile; HR, 3.3; 95% CI, 1.3-8.2; P = .01) or high anti-ADAMTS13 IgG (>75th percentile; HR, 2.6; 95% CI, 1.0-6.5; P = .047) at clinical response or remission was also predictive of exacerbation or recurrence. Our results suggest the potential need for a more aggressive approach to achieve biochemical remission (ie, normalization of plasma ADAMTS13 activity, ADAMTS13 antigen, and anti-ADAMTS13 IgG) in patients with iTTP to prevent the disease recurrence.
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http://dx.doi.org/10.1182/bloodadvances.2019000939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929391PMC
December 2019

Histone-induced thrombotic thrombocytopenic purpura in zebrafish depends on von Willebrand factor.

Haematologica 2020 04 21;105(4):1107-1119. Epub 2019 Nov 21.

Divisions of Laboratory Medicine

Thrombotic thrombocytopenic purpura (TTP) is caused by severe deficiency of ADAMTS13 (A13), a plasma metalloprotease that cleaves endothelium-derived von Willebrand factor (VWF). However, severe A13 deficiency alone is often not sufficient to cause an acute TTP; additional factors may be required to trigger the disease. Using CRISPR/Cas9, we created and characterized several novel zebrafish lines carrying a null mutation in , , and both. We further used these zebrafish lines to test the hypothesis that inflammation that results in neutrophil activation and release of histone/DNA complexes may trigger TTP. As shown, zebrafish exhibit increased levels of plasma VWF antigen, multimer size, and ability of thrombocytes to adhere to a fibrillar collagen-coated surface under flow. The zebrafish also show an increased rate of occlusive thrombus formation in the caudal venules after FeCl injury. More interestingly, zebrafish exhibit ~30% reduction in the number of total, immature, and mature thrombocytes with increased fragmentation of erythrocytes. Administration of a lysine-rich histone results in more severe and persistent thrombocytopenia and a significantly increased mortality rate in zebrafish than in wildtype () ones. However, both spontaneous and histone-induced TTP in zebrafish are rescued by the deletion of These results demonstrate a potentially mechanistic link between inflammation and the onset of TTP in light of severe A13 deficiency; the novel zebrafish models of TTP may help accelerate our understanding of pathogenic mechanisms and the discoveries of novel therapeutics for TTP and perhaps other arterial thrombotic disorders.
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http://dx.doi.org/10.3324/haematol.2019.237396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109750PMC
April 2020

Apolipoprotein B100/Low-Density Lipoprotein Regulates Proteolysis and Functions of von Willebrand Factor under Arterial Shear.

Thromb Haemost 2019 Dec 7;119(12):1933-1946. Epub 2019 Sep 7.

Division of Laboratory Medicine, Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, United States.

Background:  Proteolytic cleavage of von Willebrand factor (VWF) by a plasma a disintegrin and metalloproteinase with a thrombospondin type 1 motifs, member 13 (ADAMTS13) is regulated by shear stress and binding of coagulation factor VIII, platelets or platelet glycoprotein 1b, and ristocetin to VWF.

Objective:  Current study aims to identify novel VWF binding partners that may modulate VWF functions under physiological conditions.

Methods:  A deoxyribonucleic acid aptamer-based affinity purification of VWF, followed by tandem mass spectrometry, functional, and binding assays was employed.

Results:  Apolipoprotein B100/low-density lipoprotein (apoB100/LDL) was identified as a novel VWF-binding partner. Purified apoB100/LDL was able to accelerate the proteolytic cleavage of VWF by ADAMTS13 under shear in a concentration-dependent manner. This rate-enhancing activity was dramatically reduced when apoB100/LDL was oxidized. More interestingly, the oxidized apoB100/LDL appeared to compete with native apoB100/LDL for its enhancing activity on VWF proteolysis under shear. As a control, a purified apoA1/high-density lipoprotein (apoA1/HDL) or apoB48 exhibited a minimal or no activity enhancing VWF proteolysis by ADAMTS13 under the same conditions. Both VWF and ADAMTS13 were able to bind native or oxidized apoB100/LDL with high affinities. No binding interaction was detected between VWF (or ADAMTS13) and apoA1/HDL (or apoB48). Moreover, apoB100/LDL but not its oxidized products inhibited the adhesion of platelets to ultra large VWF released from endothelial cells under flow. Finally, significantly reduced ratios of high to low molecular weight of VWF multimers with increased levels of plasma VWF antigen were detected in mice fed with high cholesterol diet.

Conclusion:  These results indicate that apoB100/LDL may be a novel physiological regulator for ADAMTS13-VWF functions.
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http://dx.doi.org/10.1055/s-0039-1696713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814363PMC
December 2019

Synergistic effects of ADAMTS13 deficiency and complement activation in pathogenesis of thrombotic microangiopathy.

Blood 2019 09 13;134(13):1095-1105. Epub 2019 Aug 13.

Division of Laboratory Medicine, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL; and.

Severe deficiency of plasma ADAMTS13 activity is the primary cause of thrombotic thrombocytopenic purpura (TTP) whereas overwhelming activation of complement via an alternative pathway results in atypical hemolytic uremic syndrome (aHUS), the prototypes of thrombotic microangiopathy (TMA). However, clinical and pathogenic distinctions between TTP and aHUS are often quite challenging. Clinical reports have suggested that complement activation may play a role in the development of TTP, which is caused by severe deficiency of plasma ADAMTS13 activity. However, the experimental evidence to support this hypothesis is still lacking. Here, we show that mice with either or a heterozygous mutation of complement factor H (cfh) at amino acid residue of 1206 (ie, ) alone remain asymptomatic despite the presence of occasional microvascular thrombi in various organ tissues. However, mice carrying both and exhibit thrombocytopenia, low haptoglobin, increased fragmentation of erythrocytes in peripheral blood smear, increased plasma levels of lactate dehydrogenase activity, blood urea nitrogen, and creatinine, as well as an increased mortality rate, consistent with the development of TMA. Moreover, mice with a homozygous mutation of (ie, ) with or without developed severe TMA. The mortality rate in mice with was significantly higher than that in mice with alone. Histological and immunohistochemical analyses demonstrated the presence of disseminated platelet-rich thrombi in terminal arterioles and capillaries of major organ tissues in these mice that were either euthanized or died. Together, our results support a synergistic effect of severe ADAMTS13 deficiency and complement activation in pathogenesis of TMA in mice.
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http://dx.doi.org/10.1182/blood.2019001040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764266PMC
September 2019

Human neutrophil peptide-1 inhibits thrombus formation under arterial flow via its terminal free cysteine thiols.

J Thromb Haemost 2019 04 13;17(4):596-606. Epub 2019 Mar 13.

Division of Laboratory Medicine, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.

Essentials Biological activity of human neutrophil peptide (HNP)-1 in hemostasis under physiological conditions is not fully understood. HNP-1 inhibits the adhesion/aggregation of murine platelets on a fibrillar collagen surface or an activated endothelial cell surface under flow. The anti-adhesion activity appears to depend on the terminal free thiols of HNP-1, which may inhibit VWF-VWF lateral associations. Our results suggest a protective role and potential novel therapeutic use of HNP-1 for arterial thrombosis. SUMMARY: Background Human neutrophil peptides (HNPs), also known as α-defensins, are released from degranulated neutrophils and play an important role in innate immunity. However, their biological roles in hemostasis under flow are not fully explored. Objective This study aims to determine the role of HNP-1 on platelet adhesion and aggregation on a collagen surface or ultra large von Willebrand factor (ULVWF) on endothelium under flow and elucidate the structural elements required for its activity. Methods Anticoagulated whole blood from wild-type or Adamts13 mice was incubated with a fluorescein-conjugated anti-human CD41 in the presence of increasing concentrations of a synthetic HNP-1 and perfused over a collagen surface or a tumor necrosis factor (TNF)-α activated murine endothelial cell surface under arterial flow. The rate of accumulation and the final surface coverage of fluoresceinated murine platelets or the rate of forming platelet-decorated ULVWF strings were determined using the BioFlux microfluidic system. Results HNP-1 inhibited the rate and final coverage of fluorescein-labeled murine platelets on a fibrillar collagen surface under flow (100 dyne/cm ) in a concentration-dependent manner and the anti-adhesive activity of HNP-1 depended on its terminal free cysteine thiols. HNP-1 (20 μM) also dramatically inhibited the formation of platelets-decorated ULVWF strings on TNF-α activated murine endothelial surface under arterial flow. Conclusions Our results demonstrate for the first time an antiplatelet adhesion or antithrombotic activity of HNP-1; this activity depends on its terminal free thiols, likely affecting VWF-VWF lateral associations. These findings may suggest a potential novel therapeutic strategy for arterial thrombosis.
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http://dx.doi.org/10.1111/jth.14407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443439PMC
April 2019
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